Targeting Neoantigens in Triple Negative Breast Cancer

针对三阴性乳腺癌的新抗原

• 批准号: 10675496
• 负责人: William E. Gillanders
• 金额: $ 62.51万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675496
• 关键词: 4T1; Adenovirus Vector; Adjuvant Chemotherapy; Adoptive Cell Transfers; Aftercare; Algorithms; Breast Cancer Model; Breast Cancer Patient; CSF1 gene; CSF1R gene; Cancer Center; Clinical; Clinical Research; Communicable Diseases; DNA Vaccines; Data; Disease; Embryo; Enrollment; Epitopes; Evaluation; Generations; HIV vaccine; Histocompatibility Antigens Class II; Human; Immune response; Immunotherapy; Inflammatory; Lymphoid; Macrophage; Malignant Neoplasms; Modeling; Modernization; Mus; Myelogenous; Myeloid Cells; Neoadjuvant Therapy; Outcome; Patients; Peptide Vaccines; Phase I Clinical Trials; Phenotype; Population; Pre-Clinical Model; Property; Publications; Randomized; Recombinants; Reporting; Series; Source; T cell response; Testing; Tissues; Tumor Immunity; Tumor Promotion; Tumor-associated macrophages; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Validation; anti-PD-L1; antigen-specific T cells; arm; cancer clinical trial; cancer immunotherapy; design; enzyme linked immunospot assay; high dimensionality; immune checkpoint blockade; improved; innovation; innovative technologies; malignant breast neoplasm; manufacture; monocyte; mouse model; neoantigen vaccination; neoantigen vaccine; neoantigens; next generation sequencing; peripheral blood; phase I trial; plasmid DNA; preclinical study; prediction algorithm; recombinant adenovirus; recruit; response; restraint; single-cell RNA sequencing; trial comparing; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; vaccine platform; vaccine strategy; vaccine trial; vector vaccine

PROJECT SUMMARY/ABSTRACT Neoantigens have been identified by us and others as important targets of immunotherapy in the context of checkpoint blockade therapy, adoptive cell therapy, and vaccine therapy. We have recently initiated two phase 1 clinical trials of first generation neoantigen vaccines in breast cancer based on the neoantigen DNA vaccine and synthetic long peptide vaccine platforms. In preclinical models, we have optimized sequencing and epitope prediction algorithms for the identification and prioritization of neoantigens, and we have leveraged innovative technologies (CyTOF, single cell RNA sequencing) to comprehensively interrogate the immune response to neoantigen vaccination and other cancer immunotherapies. We propose to build on these observations by performing a randomized phase 1 trial of neoantigen DNA vaccine alone vs. neoantigen DNA vaccine plus anti-PD-L1, in patients with persistent triple negative breast cancer (TNBC) following neoadjuvant chemotherapy. The overall hypothesis is that enhancing neoantigen-specific T cell responses can improve clinical outcomes in TNBC. This hypothesis will be tested by completing the following aims: Specific Aim 1. Test the hypothesis that neoantigen vaccines +/- anti-PD-L1 can induce and/or enhance neoantigen-specific T cell responses. We have recently initiated a randomized phase 1 clinical trial of neoantigen DNA vaccines +/- anti-PD-L1 in TNBC patients with persistent disease following neoadjuvant chemotherapy. Next-generation sequencing and epitope prediction algorithms will be used to prioritize neoantigens. Neoantigen DNA vaccines will be designed and manufactured in the GMP facility at SCC. Specific Aim 2: Test the hypothesis that targeting tumor-associated macrophages (TAM) can enhance neoantigen-specific T cell responses in TNBC. Both embryonically-derived tissue-resident TAM and inflammatory monocyte-derived TAM restrain antitumor immunity in TNBC. We propose to combine CSF1/CSF1R blockade with CCR2 inhibition to simultaneously target both sources of TAM in the context of neoantigen vaccination in two mouse breast cancer models. The tumor microenvironment will be characterized by CyTOF and single cell RNA sequencing. Specific Aim 3: Test the hypothesis that a neoantigen simian Ad vector vaccine "prime" followed by a neoantigen DNA vaccine "boost" can enhance the response to breast cancer neoantigens. We propose a "prime/boost" strategy consisting of a simian recombinant Ad vaccine "prime," followed by a plasmid DNA vaccine "boost." This "prime/boost" neoantigen vaccine strategy represents a state-of-the-art vaccine strategy to more effectively induce antitumor immunity, and leverages expertise at WUSM within the fields of neoantigen DNA vaccines and recombinant Ad vector vaccines. Photocleavable tetramer analysis, CyTOF, and single cell RNA sequencing will be performed on neoantigen-specific T cells in the peripheral blood and the tumor microenvironment to rigorously evaluate the neoantigen-specific T cell response to vaccination.

项目摘要/摘要 在 检查点封锁治疗，养细胞疗法和疫苗疗法。我们最近开始了两个阶段 1基于新抗原DNA疫苗的乳腺癌中第一代新抗原疫苗的临床试验 和合成长肽疫苗平台。在临床前模型中，我们优化了测序和表位 用于识别和优先考虑新抗原的预测算法，我们利用了创新性 技术（细胞，单细胞RNA测序），以全面询问免疫反应 新抗原疫苗接种和其他癌症免疫疗法。我们建议通过 单独对新抗原DNA疫苗进行随机1期试验与新抗原DNA疫苗加上 抗PD-L1，在新辅助后持续三重阴性乳腺癌（TNBC）的患者中 化学疗法。总体假设是增强新抗原特异性T细胞反应可以改善 TNBC的临床结果。该假设将通过完成以下目的来检验： 特定目的1。检验新抗原疫苗+/-抗PD-L1的假设可以诱导和/或增强 新抗原特异性T细胞反应。我们最近启动了一项随机1阶段的临床试验 NeoAdjuvant后TNBC患者的Neoantigen DNA疫苗+/-抗PD-L1患者 化学疗法。下一代测序和表位预测算法将用于优先级 新抗原。新抗原DNA疫苗将在SCC的GMP设施中设计和制造。 特定目标2：检验靶向肿瘤相关巨噬细胞（TAM）的假设可以增强 TNBC中的新抗原特异性T细胞反应。两者都是胚胎衍生的组织居民TAM和 炎症单核细胞衍生的TAM在TNBC中抑制抗肿瘤免疫。我们建议结合 CCR2抑制CSF1/CSF1R阻断，以同时针对TAM的两个来源 两种小鼠乳腺癌模型中的新抗原疫苗接种。肿瘤微环境将被描述 通过细胞和单细胞RNA测序。 特定目的3：检验一个假设，即新抗原拟南芥AD矢量疫苗“ Prime”，其次是 新抗原DNA疫苗“增强”可以增强对乳腺癌新抗原的反应。我们建议 由猿猴重组AD疫苗组成的“ Prime/Boost”策略，然后是质粒DNA 疫苗“增强”。这种“ Prime/Boost” Neoantigen疫苗策略代表了最先进的疫苗策略 更有效地诱导抗肿瘤免疫，并在WUSM领域中利用专业知识 新抗原DNA疫苗和重组AD载体疫苗。可光四聚体分析，cytof， 单细胞RNA测序将在周围血液中的新抗原特异性T细胞上进行， 肿瘤微环境严格评估新抗原特异性T细胞对疫苗接种的反应。

项目成果

Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion.

• DOI: 10.1186/s12885-021-08239-z
• 发表时间: 2021-05-12
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Sankpal NV;Brown TC;Fleming TP;Herndon JM;Amaravati AA;Loynd AN;Gillanders WE
• 通讯作者: Gillanders WE